The repeated use of the same antibiotics has led to increased bacterial resistance to known methods of treatment. As a result of these increases in resistance, some bacterial infections have become difficult to treat with known antibiotics or have become untreatable. New techniques are being developed in order to cause bacterial cell apoptosis, or prevent bacterial cell proliferation in strains of bacteria that have already developed a resistance to conventional antibiotics. For example, some methods of treatment involve the disruption of various mechanisms pertinent to bacterial cell growth or survival. One such mechanism is induced by type II topoisomerases.
Type II topoisomerases are ATP-consuming enzymes that cut both strands of a DNA helix simultaneously in order to manage DNA tangles and supercoils. Once cut, the ends of the DNA are separated, and a second DNA duplex is passed through the break of the separated DNA strand. Following passage, the cut DNA is religated. This reaction allows type II topoisomerases to increase or decrease the linking number of a DNA loop by two units, and it promotes chromosome disentanglement which is necessary for cell survival if other enzymes are to transcribe the sequences that encode proteins, or if the chromosomes are to be replicated.
Disruption of the essential mechanism of such topoisomerases leads to cell death. For example, DNA gyrase, a type II topoisomerase observed in Escherichia coli (“E. coli”) and most other prokaryotes, introduces negative supercoils and decreases the linking number of DNA strands by 2 and is further able to remove knots from the bacterial chromosome thus providing necessary functions for E. coli cell growth. Some small molecules targeting type II topoisomerases are able to prevent or inhibit this mechanism induced by DNA gyrase and prevent the proliferation of bacterial cells.
Small molecules which target type II topoisomerase are divided into two classes: inhibitors and poisons. Inhibitors, such as mitindomide, work as non-competitive inhibitors of ATPase and prevent the separation of DNA induced by topoisomerases (i.e. decatenation activity). Poisons, which include etoposide, novobiocin, quinolones (including ciprofloxacin), and teniposide, target the DNA-protein complex in ways other than inhibition. Some poisons cause increased cleavage, whereas others, such as etoposide, inhibit religation of the DNA strands. Some fluoroquinolones selectively inhibit the topoisomerase II ligase domain, leaving the two nuclease domains intact. This modification, coupled with the constant action of the topoisomerase II in the bacterial cell, leads to DNA fragmentation via the nucleoside activity of the intact enzyme domains. Other fluoroquinolones are more selective for topoisomerase IV ligase domain, with enhanced Gram-positive activity. Some poisons of type II topoisomerases can target prokaryotic and eukaryotic enzymes preferentially. This may cause drug-resistant bacterial mutants to cluster around the active site for poisons leading to increasing amounts of strains resistant to the anti-bacterial medication.
There is a need in the art to develop novel antibiotics that are useful in treating or preventing bacterial infections in a subject in need thereof. The present invention meets this need.